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Background and study aims Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has emerged as an important method for obtaining a preoperative tissue diagnosis for suspected cholangiocarcinoma. However, doubts remain about test sensitivity. This study assessed the value and limitations of EUS-FNA in clinical practice. Patients and methods Patients undergoing EUS-FNA for biliary strictures/masses at a UK tertiary referral center from 2005 to 2014 were prospectively enrolled. Data on EUS-FNA findings, histology, and endoscopy and patient outcomes were collected to evaluate test performance and identify factors predictive of an inaccurate diagnostic result. Results Ninety-seven patients underwent a total of 112 EUS-FNA procedures. Overall test sensitivity for an initial EUS-FNA for suspected cholangiocarcinoma was 75 % (95 % CI 64 %–84 %), with specificity 100 % (95 % CI 85 %–100 %) and negative predictive value 0.62 (95 % CI 0.47–0.75). Hilar lesions, the presence of a biliary stent, and a diagnosis of PSC were significantly independently associated with an inaccurate result. For the most difficult cases, repeat sampling and use of the Papanicolaou cytopathology grading scale led to an increase in test sensitivity from 17 % to 100 % (P = 0.015) with no loss of specificity. Conclusions EUS-FNA was found to be a useful method for obtaining a preoperative tissue diagnosis for patients with suspected cholangiocarcinoma. This study identified markers that can reduce test accuracy and measures that can improve test performance of EUS-FNA.

Purpose A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. Methods Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). Results Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30–1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. Conclusion The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.

Tragically, many of the infections and deaths recorded in the global coronavirus disease 2019 (COVID-19) pandemic have occurred in healthcare workers. Some have attributed this to inadequate provision of personal protective equipment (PPE). In the UK, several organisations have voiced their concerns that the national PPE guidance issued by Public Health England is inadequate. Despite recent revisions to these guidelines, concerns remain that they offer insufficient protection to frontline NHS healthcare workers. In this report, we evaluate whether these concerns are merited, through critical appraisal of the available evidence, review of international PPE guidance, and consideration of the ethical implications.

BackgroundMany central initiatives to improve digital maturity and interoperability in the NHS started after 2015. There are few prior assessments of digital maturity and interoperability.MethodsFreedom of Information Act requests were sent to all English Acute NHS Trusts and Clinical Commissioning Groups (CCGs) to obtain information regarding digital maturity according to the Healthcare Information and Management Systems Society (HIMSS) Electronic Medical Record Adoption Mode (EMRAM) scale, and interoperability.ResultsOne third of Acute NHS Trusts have an EMR that meets requirements for EMRAM stage 6 or above. 17.4% of responding Trusts considered this. 59.1% of responding Trusts stated that their EMR allows for functional interoperability with other (interoperable) EMRs. The majority of responding Trusts had not conferred with other Trusts when making EMR purchasing decisions.DiscussionIn order to realise the benefits of digitisation and interoperability, we discuss policy recommendations including actions for local health economies.

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition arising due to complex interactions between multiple genetic and environmental factors. Despite recent advances, the pathogenesis of the condition is not fully understood and patients still experience suboptimal clinical outcomes. Over the past few years, investigators are increasingly capturing multi-omics data from patient cohorts to better characterise the disease. However, reaching clinically translatable endpoints from these complex multi-omics datasets is an arduous task. Network biology, a branch of systems biology that utilises mathematical graph theory to represent, integrate and analyse biological data through networks, will be key to addressing this challenge. In this narrative review, we provide an overview of various types of network biology approaches that have been utilised in IBD including protein-protein interaction networks, metabolic networks, gene regulatory networks and gene co-expression networks. We also include examples of multi-layered networks that have combined various network types to gain deeper insights into IBD pathogenesis. Finally, we discuss the need to incorporate other data sources including metabolomic, histopathological, and high-quality clinical meta-data. Together with more robust network data integration and analysis frameworks, such efforts have the potential to realise the key goal of precision medicine in IBD.

Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence numerous intracellular processes in the target cells, including the secretion of other cytokines downstream. However, there are no readily available bioinformatic resources that can model cytokine - cytokine interactions. In this effort, we built a communication map between major tissues and blood cells that reveals how cytokine-mediated intercellular networks form during homeostatic conditions. We collated the most prevalent cytokines from literature, and assigned the proteins and their corresponding receptors to source tissue and blood cell types based on enriched consensus RNA-Seq data from the Human Protein Atlas database. To assign more confidence to the interactions, we integrated literature information on cell - cytokine interactions from two systems immunology databases, immuneXpresso and ImmunoGlobe. From the collated information, we defined two metanetworks: a cell-cell communication network connected by cytokines; and a cytokine-cytokine interaction network depicting the potential ways in which cytokines can affect the activity of each other. Using expression data from disease states, we then applied this resource to reveal perturbations in cytokine-mediated intercellular signalling in inflammatory and infectious diseases (ulcerative colitis and COVID-19, respectively). For ulcerative colitis, with CytokineLink we demonstrated a significant rewiring of cytokine-mediated intercellular communication between non-inflamed and inflamed colonic tissues. For COVID-19, we were able to identify inactive cell types and cytokine interactions that may be important following SARS-CoV-2 infection when comparing the cytokine response with other viruses capable of initiating a cytokine storm. Such findings have potential to inform the development of novel, cytokine-targeted therapeutic strategies. CytokineLink is freely available for the scientific community through the NDEx platform and the project github repository (https://github.com/korcsmarosgroup/CytokineLink).

Adult-onset immunoglobulin (IgA) vasculitis presenting as terminal ileitis is a rare clinical encounter which can mimic inflammatory bowel disease or infectious gastroenteritis. A high index of clinical suspicion is required to reach the correct diagnosis and to implement the appropriate management plans. Herein, we report a case of an elderly female presenting with a short history of abdominal pain, vomiting, bloody diarrhoea, fatigue and reduced appetite. Based on the blood tests and imaging, she was initially managed as having an infective or inflammatory bowel condition. Subsequently, she developed a vasculitic rash in her lower limbs with accompanying renal involvement including haematuria and sub-nephrotic range proteinuria. She underwent a renal biopsy which confirmed the diagnosis of IgA vasculitis. She was started on a course of corticosteroid therapy which induced clinical remission.

Recent work introduces a powerful new web tool that enables a faster and statistically more reliable data mining of transcriptomics and metatranscriptomics for inflammatory bowel disease (IBD) research.

Patients with inflammatory bowel disease (IBD) are known to have perturbations in microRNA (miRNA) levels as well as altered miRNA regulation. Although experimental methods have provided initial insights into the functional consequences that may arise due to these changes, researchers are increasingly utilising novel bioinformatics approaches to further dissect the role of miRNAs in IBD. The recent exponential increase in transcriptomics datasets provides an excellent opportunity to further explore the role of miRNAs in IBD pathogenesis. To effectively understand miRNA-target gene interactions from gene expression data, multiple database resources are required, which have become available in recent years. In this technical note, we provide a step-by-step protocol for utilising these state-of-the-art resources, as well as systems biology approaches to understand the role of miRNAs in complex disease pathogenesis. We demonstrate through a case study example how to combine the resulting miRNA-target gene networks with transcriptomics data to find potential disease-specific miRNA regulators and miRNA-target genes in Crohn’s disease. This approach could help to identify miRNAs that may have important disease-modifying effects in IBD and other complex disorders, and facilitate the discovery of novel therapeutic targets.

Background Ulcerative Colitis (UC) associated single nucleotide polymorphisms (SNP) are mostly in non-coding regions of the genome. Because of that, it has been challenging to determine their role in the disease onset and severity. We have previously developed an integrative workflow (termed iSNP) to understand better how these SNPs are involved in the pathogenesis of UC. Here we present a recent update both in the methodology and new results, including a new player for prediction of therapeutic escalation in UC. Methods From immunochip data of 376 UC patients of an East-Anglian, UK cohort, the SNPs were filtered for only the UC-associated ones. Then we predicted the SNPs’ effect on regulatory interactions using two complementary transcription factor-target gene prediction methods, RSAT and FIMO. SNPs were considered if the SNP was located in the promoter region of a gene or in an enhancer region of a gene defined by the HEDD database. We considered a gene ‘SNP-affected’ if the risk allele and the non-risk allele had different transcription factor binding sites detected by any of the two methods. The proteins encoded by the SNP-affected genes were mapped to the integrated and high-confidence signaling network resource OmniPath. We also identified the direct physical interactors (first-neighbours) of these SNP affected genes/proteins. We created networks for each patient separately using their individual SNP-profiles. Finally, based on these patient-specific networks, we clustered patients in an unsupervised manner. Results We found 15 UC-associated SNPs which affected transcription factor binding sites, which in turn were modulating 54 genes. From these 54 SNP affected genes, 29 coded proteins that were present in the OmniPath signaling network. The patients formed five clusters, which were significantly correlated with therapeutic escalation defined by mesalazine or other more advanced therapy (p Conclusion We updated the iSNP method by including enhancer regions and multiple transcription factor binding site prediction methods, and were able to predict that those UC patients who have a VEGF-affecting SNP require therapeutic upscaling.

Background During inflammatory bowel disease the mucosal immune system is altered. The mucosal immune cells are communicating through the various cytokines. Single cell and small volume RNA-seq and proteomics approaches make the investigation of cytokine networks plausible However the lack of specific resources make such efforts hard. Methods To address this need in this project, we built a cell-cell communication map, CytokineLink, which collates cytokine mediated intercellular interactions. CytokineLink collects the cytokine-cytokine receptor interactions from the OmniPath, immuneXpresso and immunoGlobe databases. We demonstrate the applicability of CytokineLink by presenting how cytokine feedback loops are built and altered during Ulcerative Colitis. We mapped single-cell RNA-seq expression data from inflamed and uninflamed Ulcerative Colitis biopsies to the interactions between cytokines and cytokine receptors, and then we compared the specific cytokine-mediated cell-cell interactions. Results Using our approach, we were able to point out major differences in cell-cell communication between inflamed and uninflamed conditions, and identify key cytokine changes. For example, the generally anti-inflammatory cytokine IL-10 is produced by regulatory T-cells in both conditions. However the IL-10 receptor positive cells are altered between the inflamed and uninflamed condition: dendritic cells and innate lymphocytes did not express the receptor in the sufficient amount. It suggests that not the cytokine level directly but the receptor level alterations are involved in ulcerative colitis. Also the chemokine CXCL12 was expressed by the inflammatory fibroblasts. This cytokine promotes the T-cell recruitment and through that inflammation. Conclusion With CytokineLink, researchers are capable to pinpoint the most important interactions in the changing mucosal immune system and propose novel therapeutic approaches. We are currently developing a website and easy to follow workflows to make CytokineLink available.

Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence numerous intracellular processes in the target cells, including the secretion of other cytokines downstream. However, there are no readily available bioinformatic resources that can model cytokine–cytokine interactions. In this effort, we built a communication map between major tissues and blood cells that reveals how cytokine-mediated intercellular networks form during homeostatic conditions. We collated the most prevalent cytokines from the literature and assigned the proteins and their corresponding receptors to source tissue and blood cell types based on enriched consensus RNA-Seq data from the Human Protein Atlas database. To assign more confidence to the interactions, we integrated the literature information on cell–cytokine interactions from two systems of immunology databases, immuneXpresso and ImmunoGlobe. From the collated information, we defined two metanetworks: a cell–cell communication network connected by cytokines, and a cytokine–cytokine interaction network depicting the potential ways in which cytokines can affect the activity of each other. Using expression data from disease states, we then applied this resource to reveal perturbations in cytokine-mediated intercellular signalling in inflammatory and infectious diseases (ulcerative colitis and COVID-19, respectively). For ulcerative colitis, with CytokineLink, we demonstrated a significant rewiring of cytokine-mediated intercellular communication between non-inflamed and inflamed colonic tissues. For COVID-19, we were able to identify cell types and cytokine interactions following SARS-CoV-2 infection, highlighting important cytokine interactions that might contribute to severe illness in a subgroup of patients. Such findings have the potential to inform the development of novel, cytokine-targeted therapeutic strategies. CytokineLink is freely available for the scientific community through the NDEx platform and the project github repository.

RATIONALE AND OBJECTIVE To evaluate the relationship between receipt of annual physicals and the receipt of provider recommendation for preventive services, during a period when Medicare did not cover annual physicals (before 2011). METHODS Electronic medical records of patients aged 65 years and older from a US health care system were extracted for the 2001 to 2007 period. A fixed-effects logistic model was used to assess the relationship between receipt of periodic health examination (PHE) and receipt of provider recommendation for mammogram screening for 6466 female Medicare beneficiaries. Logistic regression models were used to assess the relationship between receipt of PHE and receipt of provider recommendation for colonoscopy screening and pneumococcal vaccination for 10 318 Medicare beneficiaries. Nine primary care providers from the network were also interviewed, selected by random sampling stratified by care model. RESULTS Electronic medical record analyses suggest that patients with a PHE were more likely to obtain provider recommendations for mammogram screening (OR = 2.17, P

Introduction The intestinal epithelium is comprised of a single layer of cells which serves a number of critical functions including the formation of a physical barrier to environmental pathogens and chemical substances, and the absorption of essential nutrients, electrolytes and water. It is also the site of the gut microbiota, a complex and diverse community of bacteria, viruses and fungi, which exists in a mutually beneficial relationship with the human host. The epithelial barrier is maintained through tightly regulated processes of stem cell renewal, epithelial maturation, cell migration and cell death. Failure to finely coordinate these processes can lead to disease states such as cancer. In this study, we aimed to investigate and characterise the role of the intestinal microbiota on epithelial cell proliferation. Methods We determined the rates of epithelial proliferation in the intestines of Specific-Pathogen-Free (SPF) mice and Germ-Free (GF) mice. We utilised a previously described method which integrates cell tracking using the thymidine analogue Bromodeoxyuridine (BrdU) in crypt-villus units, with a tailored mathematical model, to assess the spatiotemporal dynamics of epithelial cell behaviour in SPF and GF conditions. Results The rate of epithelial cell production in GF conditions was significantly slower in the colon, ileum and jejunum in comparison to SPF conditions. In the duodenum, there were no significant differences in proliferation rates in GF and SPF conditions. Cell production rates progressively decreased towards the distal part of the intestine, which inversely correlate with the concentration of organisms constituting the intestinal microbiota. Conclusions These findings indicate that the gut microbiota plays an important role in determining intestinal epithelial cell proliferation rates. This relationship may have important implications in conditions such as colorectal cancer and inflammatory bowel disease, where differences in microbial signatures are known to exist. In turn, it may be possible to harness this knowledge to alter disease progression by modifying the host microbiota.

Introduction Owing to concerns regarding their efficacy and safety, the use of probiotics for the prevention of necrotising enterocolits (NEC) remains a hotly debated topic amongst neonatologists. Despite previous meta-analyses consistently showing that probiotics prevent NEC, randomised controlled trials (RCTs) continue to demonstrate conflicting results regarding the efficacy of probiotics. Here we present the largest and most comprehensive meta-analysis to date, and the first to use a random-effects model, to investigate the efficacy of probiotics in very-low-birth-weight (VLBW) infants. We also attempt to explain for the first time the apparent heterogeneity in results from RCTs by performing meta-regression and sub-group analysis to identify particular probiotic agents and other measured variables that may significantly influence the outcome. Method PubMed/MEDLINE, EMBASE and the Cochrane Library databases were searched for studies published before 01/08/2016. Only RCTs involving VLBW infants with outcomes of NEC stage ≥2 and mortality were selected. All studies were independently scored to quantitatively assess the methodological quality. A minimum Jadad score of 3 had to be achieved for a study to be included in the analysis. 23 RCTs were identified. Data from these studies were pooled using a random-effects model for the meta-analysis and meta-regression analysis. Results Probiotics significantly reduced the incidence of NEC stage ≥2 (RR=0.57 [95% CI 0.43–0.74, p Conclusion This analysis shows with considerable statistical confidence that probiotics prevent NEC and reduce mortality in VLBW infants. We have identified that differences in probiotic agents and the influence of prenatal steroids and feeding regimens may explain the differences in outcomes between studies. Our findings support further scientific investigation and ultimately a strain-specific meta-analysis to identify an effective probiotic protocol. Disclosure of Interest None Declared

We performed an updated meta-analysis incorporating the results of recent randomised controlled trials (RCTs) to measure the effectiveness of probiotic supplementation in preventing necrotizing enterocolitis (NEC) and death in very-low-birth-weight (VLBW) infants, and to investigate any differences in efficacy by probiotic agent. Using meta-regression analysis, we assessed the contribution of other measured variables on the overall effect size and between-study variability. Conclusion Overall, probiotics lead to significant reductions in NEC incidence and mortality in VLBW infants. Differences in probiotic agents and the influence of prenatal steroids and feeding regimens may explain the differences in outcomes between studies. This article is protected by copyright. All rights reserved.

In a 2012 meeting at the Centers for Disease Control and Prevention (CDC), key experts and stakeholders identified public health knowledge gaps about congenital heart defects (CHDs), namely prevalence of CHDs across the life span, long‐term outcomes of persons with CHDs, and health services

Background . Achieving adequate systemic oxygen delivery after the Norwood procedure frequently is complicated by excessive pulmonary blood flow at the expense of systemic blood. We hypothesized that phenoxybenzamine could achieve a balanced circulation through reduction of systemic vascular resistance. Methods . In this prospective, nonrandomized study, oximetric catheters were placed in the superior vena cava for continuous monitoring of systemic venous oxygen saturation. Postoperative hemodynamic variables were compared between 7 control patients and 8 patients who received phenoxybenzamine. Results . The hospital survival rate was 93% (14 of 15 patients). Improvements in postoperative hemodynamics in the phenoxybenzamine group included a higher systemic venous oxygen saturation, a narrower arteriovenous oxygen content difference, a lower ratio of pulmonary to systemic flow, and a lower indexed systemic vascular resistance. In the phenoxybenzamine group, mean arterial blood pressure was related directly to systemic oxygen delivery, in contrast to the control group, where mean arterial pressure was related directly to indexed systemic vascular resistance and the ratio of pulmonary to systemic circulation. Conclusions . Continuous postoperative monitoring of systemic venous oxygen saturation in a patient who has undergone the Norwood procedure provides early identification of low systemic oxygen delivery and an elevated ratio of pulmonary to systemic circulation. In this pilot study, phenoxybenzamine appeared to improve systemic oxygen delivery during the early postoperative period after the Norwood procedure. Further studies are indicated to confirm these results.

Background. To determine factors predicting mortality and morbidity after repair of complete atrioventricular septal defect, we retrospectively analyzed preoperative, operative, and postrepair factors on the outcome of 115 consecutive complete atrioventricular septal defect repairs at The Children's Hospital of Wisconsin between January 1974 and December 1993. Methods. For the entire experience the operative mortality was 13.9% (16 patients). During the most recent era, January 1988 to December 1993, operative mortality was 3.6% (2 of 55 patients). This was significantly improved from the two previous eras, January 1974 to December 1980, 28% (7 of 25) and January 1981 to December 1987, 20% (7 of 35 patients) ( p = 0.02). There were seven late deaths; 10-year actuarial survival, including operative mortality was 81%. Age at complete repair decreased; before 1982 all patients were more than 12 months of age, whereas after 1982 64% (56 of 88 patients) were 12 months of age or less. Results. Moderate or severe preoperative left atrioventricular valve regurgitation was not a risk factor for operative mortality. For operative survivors with moderate to severe preoperative left atrioventricular valve regurgitation (n = 17), late postoperative left atrioventricular valve regurgitation (follow-up data available on 15 patients) was significantly reduced (severe = 1, moderate=5, mild=9; p = 0.007). Conclusions. Early mortality was predicted by the era of surgical repair. Conversion to routine repair during infancy was achieved with a simultaneous decrease in operative mortality. For patients with moderate to severe preoperative left atrioventricular valve regurgitation, significant improvement in the degree of left atrioventricular valve regurgitation can be expected without an increase in operative or late mortality or morbidity.

Systems Theoretic Process Analysis (STPA) is a powerful new hazard analysis method designed to go beyond traditional safety techniques - such as Fault Tree Analysis (FTA) - that overlook important causes of accidents like flawed requirements, dysfunctional component interactions, and software errors. While proving to be very effective on real systems, no formal structure has been defined for STPA and its application has been ad-hoc with no rigorous procedures or model-based design tools. This report defines a formal mathematical structure underlying STPA and describes a procedure for systematically performing an STPA analysis based on that structure. A method for using the results of the hazard analysis to generate formal safety-critical, model-based system and software requirements is also presented. Techniques to automate both the analysis and the requirements generation are introduced, as well as a method to detect conflicts between the safety and other functional model-based requirements during early development of the system.

Although occasional long-term survival without surgical intervention is possible, for most patients with single-ventricle anatomy (SVA), the natural history is dismal. 20 Even patients who manage to survive long term without surgical intervention develop the late sequelae of cyanosis and frequently have depressed ventricular function secondary to volume load and cyanosis. 1 A Fontan procedure is the treatment goal for patients with SVA. The Fontan operation and related procedures, described by Fontan and Baudet, 18 Kruetzer et al, 34 and Glenn, 26 are also known as right heart bypass procedures. Initially, right heart bypass procedures were applied to patients with right heart obstruction, most commonly tricuspid atresia (Fig. 1). These procedures bypass the obstructed right ventricle, connecting systemic venous return directly to the pulmonary arteries. The goal of the Fontan procedure is to connect systemic venous return (superior [SVC] and inferior vena cava [IVC]) with the pulmonary arteries and provide adequate pulmonary blood flow and cardiac output with minimal elevation of the systemic venous pressure. The Fontan procedure separates the systemic and pulmonary venous returns, relieves cyanosis, and decreases the volume load of the single ventricle. The Fontan procedure, therefore, achieves as closely as possible a normal circulatory pattern for patients with SVA. Multiple forms of congenital heart disease are unsuitable for two-ventricle repair, but no one classification system exists. Although Fontan palliation is the ultimate goal for patients with tricuspid atresia, hypoplastic left heart syndrome, and other single ventricles of varying anatomy, these lesions and the outcome of surgical intervention are frequently reported separately in the literature. The particular anatomic subtype is clearly important in forming a plan for neonatal palliation and may have an impact on the long-term outcome as well; however, all patients for whom two-ventricular repair is not possible share common risk factors for early and late survival. For example, systemic outflow obstruction is always a component of hypoplastic left heart syndrome but can also occur with tricuspid atresia, and the surgical intervention may be the same. The anatomic subtype and the particular form of maldevelopment are less important than the identification of anatomy unsuitable for two-ventricle repair. Isolated hypoplasia or atresia of the outlet portion of either ventricle does not rule out a two-ventricle repair. Single-ventricle palliation is required for atresia or significant hypoplasia of either of the atrioventricular valves, severely unbalanced atrioventricular canal, or significant hypoplasia of either ventricle. The term SVA is used for the condition of patients with a functional single ventricle regardless of the anatomic subtype. A standardized, staged approach to the management of patients with SVA ensures better preparation for the Fontan procedure and should improve long-term outcome. Effective neonatal or early infant palliation is the first and most critical stage. During the neonatal or early infant period, the goal is complete relief of systemic obstruction and appropriate limitation of pulmonary blood flow to achieve balanced circulation. Subsequent stages include a bidirectional cavopulmonary anastomosis (BDCPA), which is an anastomosis of the superior vena cava to the confluent pulmonary arteries. Later, the Fontan procedure is completed by connecting the inferior vena cava return to the pulmonary arteries. Following the completion Fontan procedure, central venous pressure is the force that drives pulmonary blood flow. Systemic output is derived from the pulmonary venous return. In this circuit, individual pressure gradients combine to elevate central venous pressure. Severe elevation of the gradient between the systemic vein and the pulmonary atrium results in intolerable elevation of central venous pressure and restrictive ventricular preload, resulting in reduced cardiac output. Risk factors for failure of the Fontan physiology include poor ventricular function with elevated end-diastolic pressure, insufficiency of the atrioventricular valve, elevated pulmonary vascular resistance, pulmonary artery distortion, and stenosis of the systemic venous to pulmonary artery connections. 10,31,32 The goal of the staged approach to patients with SVA is to minimize the risk factors for subsequent Fontan palliation.